Topical pharmaceutical compositions

ABSTRACT

Topical pharmaceutical compositions are described comprising, based on the total weight of the composition: a) 0.01 to 0.2 wt. % of mometasone furoate, b) 5 to 18 wt. % of hexylene glycol, c) 20 to 40 wt. % of water, and d) 25 to 70 wt. % of an oil phase. Said compositions are stable and can be safely and easily applied over large surface areas of the skin in an acceptable way by the general patient population for the treatment or prevention of psoriasis, atopic dermatitis (atopic eczema) and other skin disorders or diseases.

FIELD OF THE INVENTION

The present invention relates to topical pharmaceutical compositionscomprising mometasone furoate. Said compositions are stable and can besafely and easily applied over large surface areas of the skin in anacceptable way by the general patient population. The invention furtherrelates to a process for the preparation of said compositions and tomethods of treatment by administering the compositions.

BACKGROUND OF THE INVENTION

Topical corticosteroids, as a class, demonstrate anti-inflammatory,anti-pruritic and vasoconstrictive actions. They are generally used torelieve the redness, skin edema (swelling), itching, crusting, flaking,blistering, cracking, oozing and discomfort of psoriasis, atopicdermatitis (atopic eczema) and other pathologies of the skin likecontact dermatitis, seborrheic dermatitis, xerotic eczema, discoideczema, venous eczema, dermatitis herpetiformis, neurodermatitis orautoeczematization.

Commercially, topical corticosteroid products are available asointments, creams, solutions, foams and lotions. The Food and DrugAdministration (FDA), Center for Drug Evaluation and Research (CDER)Data Standards Manual, Dosage Form (version 08) defines ointment as “asemisolid dosage form, usually containing less than 20% water andvolatiles and more than 50% hydrocarbons, waxes, or polyols as thevehicle, which is generally for external application to the skin ormucous membranes”; cream as “an emulsion, semisolid dosage form, usuallycontaining more than 20% water and volatiles and/or less than 50%hydrocarbons, waxes, or polyols as the vehicle, which is generally forexternal application to the skin or mucous membranes”; and lotion as “anemulsion, liquid dosage form, which is generally for externalapplication to the skin”.

Due to their physico-chemical properties lotions are more pleasant to beused (cosmetically accepted) to the end-user than ointments or creams,e.g. lotions are easily applied than ointments or creams and aretypically used for the treatment of large body areas, to hair-coveredskin and on the hairy scalp.

While the mechanisms of the anti-inflammatory effects are unclear, thereappears to be a correlation between the therapeutic effects ofcorticosteroids and their vasoconstrictive potencies. Vasoconstrictorassays have been commonly used to compare and predict the relativetherapeutic potencies of topically applied corticosteroids (McKenzie A.W., Stoughton R. B.: Method for comparing percutaneous absorption ofsteroids. Arch Dermatol 1962; 86: 608-610)

Mometasone furoate is a corticosteroid commonly used in the treatment ofinflammatory skin disorders, allergic rhinitis (such as hay fever), andasthma. Mometasone furoate is a fine white to off-white powder that isinsoluble in water, slightly soluble in octanol, and moderately solublein ethyl alcohol. The exceptionally poor solubility of mometasonefuroate is a limitation for the development of topical pharmaceuticalcompositions.

Different solvents have been used in order to develop topicalpharmaceutical compositions containing mometasone furoate, eithercontaining said mometasone furoate partially dissolved and partiallysuspended or containing the drug totally dissolved due to the presenceof solubilizing agents.

Thus, U.S. Pat. No. 4,775,529 describes topical pharmaceuticalcompositions containing corticosteroids (including mometasone furoate)in a hydro-alcoholic base comprising a) 15-50 wt. % of propylene glycol,b) 20-40 wt. % of isopropyl alcohol, c) 20-60 wt. % of water, d) 0.1-3.0wt. % of a thickening agent and e) a buffer to adjust the pH between 3.0to 6.0. Other topical mometasone furoate/propylene glycol pharmaceuticalcompositions are disclosed in WO 9108733, WO2004105686 and WO2008126076.

On the other side, U.S. Pat. No. 4,808,610 discloses topicalpharmaceutical compositions comprising a) 0.01-0.25% of mometasonefuroate, b) 5-20% of hexylene glycol, c) 1.0-5.0% of water, d) 2.0-10.0%of white wax, e) 40-70% of white petrolatum and other ingredients. U.S.Pat. No. 4,808,610 indicates that when mometasone furoate is partiallydissolved and partially suspended in propylene glycol based creamformulations, the resulting formulations do not possess the necessaryefficacy; and when mometasone furoate is completely dissolved in oleylalcohol/propylene glycol based cream formulations, the resultingformulations not only lack the required activity but also are irritantin a rabbit dermal test. Additionally, according to U.S. Pat. No.4,808,610, formulations containing drug solubilizing agents may resultin poor activity.

Finally, EP 1886686 describes topical pharmaceutical compositionscomprising a) 0.01-0.2 wt. % of mometasone furoate, b) 10-90 wt. % ofwater and c) a combination of at least an aromatic alcohol and at leasta solvent selected from two different groups, and e) optionally furtheradditives. According to EP 1886686 the combination of the aromaticalcohol and the solvent increases the solubility of mometasone furoateavoiding its precipitation even in the case of increasing the watercontent.

Surprisingly, it has been found that topical pharmaceutical compositionscomprising mometasone furoate suspended in hexylene glycol basedformulations (i.e. topical pharmaceutical compositions comprising solidparticles of mometasone furoate dispersed in hexylene glycol basedformulations) are stable, exhibit an efficacy comparable to mometasonefuroate compositions available in the market and, due to itsphysico-chemical properties, are easily applied to the skin (easy tospread on the skin), in particular to hair-covered skin, absorb rapidly,not being irritant to the skin and, as a result, being more pleasant touse to the general patient population.

SUMMARY OF THE INVENTION

It has now surprisingly been found that topical pharmaceuticalcompositions comprising, based on the total weight of the composition:

a) 0.01 to 0.2 wt. % of mometasone furoate,b) 5 to 18 wt. % of hexylene glycol,c) 20 to 40 wt. % of water, andd) 25 to 70 wt. % of an oil phase,are stable and exhibit a comparable efficacy to mometasone furoatecompositions available in the market although having a higher watercontent and containing the mometasone furoate suspended (dispersed) inthe composition and not dissolved. Furthermore, due to itsphysico-chemical properties, said topical pharmaceutical compositionsare easily applied to the skin (easy to spread on the skin), inparticular to hair-covered skin, absorb rapidly, not being irritant tothe skin and, as a result, being more pleasant to use to the generalpatient population.

Additionally, patients treated with the topical pharmaceuticalcompositions of the invention presented better skin hydration values andskin adsorption times than patients treated with mometasone furoatecompositions available in the market.

The invention further relates to a composition as defined above for usein the treatment or prevention of psoriasis, atopic dermatitis (atopiceczema) and other skin disorders or diseases.

The invention further relates to the use of a composition as definedabove for the manufacture of a medicament for the treatment orprevention of psoriasis, atopic dermatitis (atopic eczema) and otherskin disorders or diseases.

The invention further relates to a method for treating a subjectafflicted with psoriasis, atopic dermatitis (atopic eczema) and otherskin disorders or diseases, which comprises applying to the affectedarea of skin of said subject an effective amount of a topicalpharmaceutical composition as defined above.

DETAILED DESCRIPTION OF THE INVENTION Mometasone Furoate

Mometasone furoate[9α,21-dichloro-11β,17-dihydroxy-16α-methylpregna-1,4-diene-3,20-dione17-(2-furoate)] is a corticosteroid having the empirical formulaC₂₇H₃₀Cl₂O₆, and a molecular weight of 521.4 g/mol.

According to the invention, preferably anhydrous mometasone furoate isused.

Anhydrous mometasone furoate is mometasone furoate that lacks anassociated water molecule. Anhydrous mometasone furoate can bedistinguished from mometasone furoate monohydrate, which is a hydratedform of mometasone furoate that has a molecular formula ofC₂₇H₃₀Cl₂O₆.H₂O.

Hexylene Glycol

Hexylene glycol (2-Methyl-2,4-Pentanediol) is a clear, colourless,viscous liquid which absorbs moisture when exposed to moist air. It ismiscible with water, alcohol, ether, chloroform, acetone, and many otherorganic solvents. Hexylene glycol has the empirical formula C₆H₁₄O₂, anda molecular weight of 118.2 g/mol.

The aqueous liquid pharmaceutical compositions

The present invention provides topical pharmaceutical compositionscomprising, based on the total weight of the composition:

a) 0.01 to 0.2 wt. % of mometasone furoate,b) 5 to 18 wt. % of hexylene glycol,c) 20 to 40 wt. % of water, andd) 25 to 70 wt. % of an oil phase.

In the topical pharmaceutical compositions according to the inventionthe amount of a) mometasone furoate, is preferably in the range of 0.05to 0.15 wt. %, more preferably 0.08 to 0.12 wt. % based on the totalweight of the composition.

The amount of compound b) hexylene glycol, is preferably in the range of7 to 15 wt. %, more preferably 8 to 13 wt. % based on the total weightof the composition.

The amount of compound c) water, is preferably in the range of 25 to 40wt. %, more preferably 25 to 35 wt. %, even more preferably 26 to 34 wt.% based on the total weight of the composition.

Preferably, the topical pharmaceutical compositions according to theinvention further comprise, based on the total weight of thecomposition, d) 25 to 70 wt. %, preferably 30 to 65 wt. %, morepreferably 35 to 45 wt. %, of an oil phase.

According to the invention, an oil is a substance that is in a viscousliquid state (“oily”) at room temperature or slightly warmer, and isboth hydrophobic (immiscible with water) and lipophilic (miscible withother oils). Suitable oil phases according to the invention arepetroleum hydrocarbons (mineral oils, paraffins and waxes), animal andvegetable fats and oils, fatty acids, fatty alcohols, natural waxes,silicones and polyols other than hexylene glycol, or mixtures thereof.

Suitable petroleum hydrocarbons, i.e. mineral oils, paraffins and waxesfrom petroleum according to the present invention are: hard paraffin,liquid paraffin (Liquid Petrolatum or Paraffinum Liquidum), light liquidparaffin (Light Liquid Petrolatum or Paraffinum Perliquidium), whitesoft paraffin (White Petrolatum), yellow soft paraffin (YellowPetrolatum), macrocrystalline paraffin waxes (which are mixtures whichconsist mainly of saturated C₁₈-C₃₀ hydrocarbons and smaller amounts ofiso-alkanes and cycloalkanes with a molecular weight comprised between250 and 450 g/mol and, although they are solids at room temperature,they have low melting points, usually comprised between 40° C. and 60°C.), microcrystalline paraffines waxes (which consist of C₄₀-C₅₅compounds which contain, in addition to normal hydrocarbons, largeamounts of iso-alkanes and naphtenes with long alkyl side-chains, theiso-alkanes forming microcrystals, the microcrystalline paraffines waxeshaving mean molecular weights comprised between 500 and 800 g/mol, beingsolids at room temperature, and having melting points comprised between60° C. and 90° C.), or mixtures thereof. Preferred petroleumhydrocarbons are hard paraffin, liquid paraffin, light liquid paraffin,white soft paraffin or mixture thereof, being particularly preferredliquid paraffin, white soft paraffin or mixtures thereof.

Suitable animal or vegetable fats and oils according to the presentinvention are esters of linear and/or branched, saturated and/orunsaturated alkanecarboxylic acids with a chain length of 1 up to 30carbon atoms and linear and/or branched, saturated and/or unsaturatedalcohols with a chain length of 1 up to 30 carbon atoms; or are estersof aromatic carboxylic acids and linear and/or branched, saturatedand/or unsaturated alcohols with a chain length of 1 up to 30 carbonatoms.

These oils can be advantageously selected from the group consisting ofisopropyl myristate, isopropyl palmitate, isopropyl stearate, isopropyloleate, n-butyl stearate, n-hexyl laurate, n-decyl oleate, isooctylstearate, isononyl stearate, isononyl isononanoate, 2-ethylhexyllaurate, 2-ethylhexyl palmitate, 2-ethylhexyl cocoate, 2-hexyldecylstearate, 2-ethylhexyl isostearate, 2-octyldodecyl palmitate, cetylpalmitate, oleyl oleate, oleyl erucate, erucyl oleate, erucyl erucate,as well as synthetic, semisynthetic and natural mixtures of such esters,such as jojoba oil (a natural mixture of esters of monounsaturatedmonocarboxylic acids with a C₁₈-C₂₄ chain with also monounsaturatedmonoalcohols and with a long C₁₈-C₂₄ chain).

Other suitable oils of the type of esters of saturated alkanecarboxylicacids and alcohols are fatty acid methyl esters, preferably C₆-C₂₄ fattyacid methyl esters from animal and vegetable fats and oils such ascotton, safflower, coconut, rapeseed, linseed, palm, palm kernel,sunflower, olein, olive, olive pomace, castor oil, tallow, soy, talloil, etc, possibly totally or partially hydrogenated, as well aspurified or synthetic fatty acids such as caproic acid, caprylic acid,capric acid, lauric acid, myristic acid, palmitic acid (cetylic acid),palmitoleic acid, stearic acid, isostearic acid, 2-ethylhexanoic acid,oleic acid, ricinoleic acid, elaidic acid, petroselinic acid, linoleicacid, linolenic acid, arachidic acid, gadoleic acid, behenic acid anderucic acid, or mixtures thereof.

Other suitable animal or vegetable fats and oils according to thepresent invention are fatty acid triglycerides, specifically triglycerinesters of linear and/or branched, saturated and/or unsaturatedalkanecarboxylic acids with a chain length of 6 up to 24 carbon atoms,preferably of 10 up to 18 carbon atoms. The fatty acids esterifying thedifferent positions of glycerin can be different, giving rise to a largeamount of possible combinations, including positional combinations. Theposition of the different fatty acids in natural triglycerides is notrandom, but rather it depends on the origin of the fat. Thetriglycerides more simple are those constituted by a sole fatty acid.

Fatty acid triglycerides can be advantageously chosen, for example, fromthe group consisting of synthetic, semi-synthetic and natural oils, asfor example, animal fats and oils such as cow tallow, pig lard, boneoil, aquatic animal fats and oils (fish, such as herring, cod orsardine; cetaceans; etc.); and vegetable fats and oils such as avocadooil, almond oil, hazelnut oil, babassu palm oil, borage oil, peanut oil,canola oil, hemp oil, milk thistle oil, safflower oil, chufa oil,coconut oil, rapeseed oil, black cumin oil, wheat germ oil, sunfloweroil, linseed oil, macadamia nut oil, corn oil, walnut oil, olive oil andits by-products such as olive pomace oil, palm oil and its fractionssuch as palm olein and palm stearin, evening primrose oil, rosehip oil,castor oil, rice bran oil, apricot kernel oil, cottonseed oil,pumpkinseed oil, palm kernel oil and its fractions such as palm kernelolein and palm kernel stearin, grape seed oil, sesame oil, soy oil,cocoa butter, shea butter and the like.

Particularly preferred are vegetable fats and oils as described above.

Suitable fatty acids according to the present invention are C₆-C₂₄ fattyacids from vegetable and animal fats and oils, such as those previouslydescribed, such as cotton, safflower, coconut, rapeseed, linseed, palm,palm kernel, sunflower, olein, olive, olive pomace, castor oil, tallow,soy, tall oil, etc, possibly totally or partially hydrogenated, as wellas purified or synthetic fatty acids such as caproic acid, caprylicacid, capric acid, lauric acid, myristic acid, palmitic (cetylic) acid,palmitoleic acid, stearic acid, isostearic acid, 2-ethylhexanoic acid,oleic acid, ricinoleic acid, elaidic acid, petroselinic acid, linoleicacid, linolenic acid, arachidic acid, gadoleic acid, behenic acid anderucic acid, or technical grade mixtures thereof. Fatty acids of thelauric, myristic, palmitic, palmitoleic, stearic, isostearic,2-ethylhexanoic, oleic, ricinoleic, behenic type, or mixtures thereofare preferred, in particular, those from vegetable origin.

Suitable fatty alcohols according to the present invention are C₆-C₂₄fatty alcohols from vegetable and animal fats and oils such as thosepreviously described, such as cotton, safflower, coconut, rapeseed,linseed, palm, palm kernel, sunflower, olein, olive, olive pomace,castor oil, tallow, soy, tall oil, etc, possibly totally or partiallyhydrogenated, as well as purified or synthetic fatty alcohols such ascaproyl alcohol, capryl alcohol, capric alcohol, lauryl alcohol,myristyl alcohol, palmytil (cetyl) alcohol, palmitoyl alcohol, stearylalcohol, isostearyl alcohol, 2-octyldodecanol, 2-ethylhexanoyl alcohol,oleyl alcohol, ricinoleyl alcohol, elaidyl alcohol, petroselinicalcohol, linoleyl alcohol, linolenyl alcohol, arachidyl alcohol,gadoleyl alcohol, behenyl alcohol and erucyl alcohol, or technical grademixtures thereof such as cetostearyl alcohol. Fatty alcohols of thelauryl, myristyl, palmityl, palmitoleyl, stearyl, isostearyl2-ethylhexanoyl, oleyl, ricinoleyl and behenyl type, or technical grademixtures thereof such as cetostearyl alcohol are preferred, inparticular, those from vegetable origin.

Suitable natural waxes according to the present invention are thecandelilla wax, carnauba wax, Japan wax, esparto wax, cork wax, guarumawax, rice wax, sugar cane wax, ouricury wax, montan wax, beeswax,shellac wax, espermaceti, wool lanolin (wax), uropygial fat wax, ceresinwaxes, peat waxes, ozokerite, as well as chemically modified waxes (hardwaxes) for example, montan wax esters, waxes obtained by theFischer-Tropsch process, hydrogenated jojoba waxes and synthetic waxes.

Silicones suitable according to the present invention are cyclic and/orlinear silicones, which can be found as monomers generally characterizedby structural elements such as:

where the silicon atoms can be substituted by alkyl or aryl radicalsequal or different, represented here generally by R₁-R₄ groups.

Linear silicones with siloxane units suitable according to the presentinvention are generally characterized by structural elements such as:

where the silicon atoms can be substituted by alkyl or aryl radicalsequal or different, are represented here in general by R₁-R₄ groups(meaning the number of different radicals is not necessarily limited to4), m can take values from 2 to 200.000.

Cyclic silicones suitable according to the present invention aregenerally characterized by structural elements such as:

where the silicon atoms can be substituted by alkyl or aryl radicalsequal or different, represented here generally by R₁-R₄ groups (meaningthe number of different radicals is not necessarily limited to 4), n cantake values of 3/2 to 20. Fractional values of n indicate that it may beodd numbers of siloxane groups present in the ring.

Specific examples include a cyclic methyl siloxane having the formula[(CH₃)₂SiO]_(x) in which x is 3-6, or short chain linear methylsiloxanes having the formula ((CH₃)₂SiO[(CH₃)₂SiO]_(y)Si(CH₃)₃ in whichy is 0-5.

Some suitable cyclic methyl siloxanes are hexamethylcyclotrisiloxanes(D3), a solid with a boiling point of 134° C. and the formula[(Me₂)SiO]₃; octamethylcyclotetrasiloxane (D4) with a boiling point of176° C., a viscosity of 2.3 mm²/s, and the formula [(Me₂)SiO]₄;decamethylcyclopentasiloxane (D5) (cyclomethicone) with a boiling pointof 210° C., a viscosity of 3.87 mm²/s, and the formula [(Me₂)SiO]₅; anddodecamethylcyclohexasiloxane (D6) with a boiling point of 245° C., aviscosity of 6.62 mm²/s and the formula [(Me₂)SiO]₆.

Some suitable short linear methyl siloxane are hexamethyldisiloxane (MM)with a boiling point of 100° C., viscosity of 0-65 mm²/s, and formulaMe₃SiOMe₃; octamethyltrisiloxane (MDM) with a boiling point of 152° C.,viscosity of 1.04 mm²/s, and formula Me₃SiOMe₂SiOSiMe₃;decamethyltetrasiloxane (MD2M) with a boiling point of 194° C.,viscosity of 1.53 mm²/s, and formula Me₃SiO(MeSiO)₂SiMe₃;dodecamethylpentasiloxane (MD3M) with a boiling point of 229° C.,viscosity of 2.06 mm²/s, and formula Me₃SiO(Me₂SiO)₃SiMe₃;tetradecamethylhexasiloxane (MD4M) with a boiling point of 245° C.,viscosity of 2.63 mm²/s, and formula Me₃SiO(Me₂SiO)₄SiMe₃; andhexadecamethylheptasiloxane (MD5M) with a boiling point of 270° C.,viscosity of 3.24 mm²/s, and formula Me₃SiO(Me₂SiO)₅SiMe₃.

Furthermore, long chain linear siloxanes such as phenyltrimethicone,bis(phenylpropyl)dimethicone, dimethicone, dimethiconol, cyclomethicone(octametilciclotetrasiloxane), hexamethylcyclotrisiloxane,poly(dimethylsiloxane), cetyldimethicone and behenoxy dimethicone arealso included.

In addition, mixtures of cyclomethicone and isotridecyl isononanoate andof cyclomethicone and 2-ethylhexyl isostearate are also suitablesilicones according to the invention.

Suitable polyols other than hexylene glycol according to the presentinvention are preferably water-soluble polyols such as polyhydricalcohols with two or more hydroxyl groups in their molecule. Specificexamples can include ethylene glycol, propylene glycol, 1,3-butyleneglycol, 1,4-butylene glycol, dipropylene glycol, polyethylene glycolwith average molecular weights by weight ranging between 100 and 1000,glucose, fructose, galactose, mannose, ribose, erythrose, maltose,maltitose, maltotriose, sucrose, xylitol, sorbitol, threitol,erythritol, glycerol, polyglycerol and starch alcohols. Preferredpolyols other than hexylene glycol are ethylene glycol, propyleneglycol, 1,3-butylene glycol, 1,4-butylene glycol, dipropylene glycol,polyethylene glycol with average molecular weights by weight rangingbetween 100 and 1000, glycerol, polyglycerol, and mixtures thereof.

Preferred topical pharmaceutical compositions of the invention comprise,based on the total weight of the composition:

a) 0.01 to 0.2 wt. %, preferably 0.05 to 0.15 wt. %, more preferably0.08 to 0.12 wt. % of mometasone furoate,b) 5 to 18 wt. %, preferably 7 to 15 wt. %, more preferably 8 to 13 wt%. of hexylene glycol,c) 20 to 40 wt. %, preferably 25 to 35 wt. %, more preferably 26 to 34wt. % of water, andd) 25 to 70 wt. %, preferably 30 to 65 wt. %, more preferably 35 to 45wt. % of an oil phase.

In a preferred embodiment, the topical pharmaceutical compositions ofthe invention comprise, based on the total weight of the composition:

a) 0.05 to 0.15 wt. %, preferably 0.08 to 0.12 wt. % of mometasonefuroate,b) 7 to 15 wt. %, preferably 8 to 13 wt. % of hexylene glycol,c) 25 to 35 wt. %, preferably 26 to 34 wt. % of water,d1) 32 to 50 wt. %, preferably 35 to 48 wt. % of petroleum hydrocarbons,d2) 5 to 12 wt. %, preferably 7 to 10 wt. % of C₆-C₂₄ fatty alcohols,andd3) 0.1 to 5 wt %, preferably 0.5 to 3 wt. % of polyols other thanhexylene glycol.

In a further preferred embodiment, the topical pharmaceuticalcompositions of the invention comprise, based on the total weight of thecomposition:

a) 0.08 to 0.12 wt. % of mometasone furoate,b) 8 to 13 wt. % of hexylene glycol,c) 26 to 34 wt. % of water,d1) 35 to 48 wt. % of petroleum hydrocarbons selected from liquidparaffin, white soft paraffin or mixtures thereof,d2) 7 to 10 wt. % of C₆-C₂₄ fatty alcohols selected from lauryl alcohol,miristyl alcohol, palmityl alcohol, stearyl alcohol, oleyl alcohol ormixtures thereof, andd3) 0.5 to 3 wt. % of glycerol.

The pH value of the topical pharmaceutical compositions according to theinvention is typically within the acceptable range for topicaladministration, and is preferably in the range of 3.0 to 6.0, morepreferably in the range of 3.5 to 5.0.

The viscosity of the topical pharmaceutical compositions according tothe invention is typically in the range of 2,000 to 15,000 mPa·s,preferably in the range of 2,500 to 10,000 mPa·s, more preferably in therange of 3,000 to 7,000 mPa·s measured at 20° C. using a DIN-RotationsRheometer (Paar Physics); Measuring System Z 3 DIN; D=57 1/s.

The topical pharmaceutical compositions according to the invention mayoptionally further comprise other well-known pharmaceutically and/orcosmetically acceptable additives, such as, e.g. anti-irritants,antioxidants, buffering agents (pH adjusting agents), chelating agents,emollients, penetration enhancing agents, preservative agents,solubilizing agents, thickening agents, wetting agents, and the like, ormixtures thereof.

Examples of suitable anti-irritants are aloe vera, chamomile,alpha-bisabolol, cola nitida extract, green tea extract, tea tree oil,licoric extract, batyl alcohol (α-octadecyl glyceryl ether), selachylalcohol (α-9-octadecenyl glyceryl ether), chimyl alcohol (α-hexadecylglyceryl ether), panthenol, allantoin, caffeine or other xanthines,glycyrrhizic acid and derivatives thereof, and mixtures thereof.

Antioxidants used can be any antioxidants which are suitable orcustomary for cosmetic and/or dermatological applications. Suitableantioxidants are advantageously selected from the group consisting ofamino acids (for example glycine, histidine, tyrosine, tryptophan) andderivatives thereof, imidazoles (e.g. urocanic acid) and derivativesthereof, peptides such as D,L-carnosine, D-carnosine, L-carnosine andderivatives thereof (e.g. anserine), carotenoids, carotenes (e.g.α-carotene, (3-carotene, lycopene) and derivatives thereof, lipoic acidand derivatives thereof (e.g. dihydrolipoic acid), aurothioglucose,propylthiouracil and other thiols (e.g. thioredoxin, glutathione,cysteine, cystine, cystamine and the glycosyl, N-acetyl, methyl, ethyl,propyl, amyl, butyl and lauryl, palmitoyl, oleyl, γ-linoleyl,cholesteryl and glyceryl esters thereof) and salts thereof, dilaurylthiodipropionate, distearyl thiodipropionate, thiodipropionic acid andderivatives thereof (esters, ethers, peptides, lipids, nucleotides,nucleosides and salts) and sulphoximine compounds (e.g. buthioninesulphoximines, homocysteine sulphoximine, buthionine sulphones, penta-,hexa-, heptathionine sulphoximine) in very small tolerated doses (e.g.pmol to μmol/kg), also (metal) chelating agents (e.g. α-hydroxy fattyacids, palmitic acid, phytic acid, lactoferrin), α-hydroxy acids (e.g.citric acid, lactic acid, malic acid), humic acid, bile acid, bileextracts, bilirubin, biliverdin, EDTA, EGTA and derivatives thereof,unsaturated fatty acids and derivatives thereof (e.g. γ-linolenic acid,linoleic acid, oleic acid), folic acid and derivatives thereof,ubiquinone and ubiquinol and derivatives thereof, vitamin C andderivatives (e.g. ascorbyl palmitate, Mg ascorbyl phosphate, ascorbylacetate), tocopherols and derivatives (e.g. vitamin E acetate), andconiferylbenzoate of benzoin, rutinic acid and derivatives thereof,ferulic acid and derivatives thereof, butylated hydroxytoluene,butylated hydroxyanisole, nordihydroguaiac resin acid,nordihydroguaiaretic acid, trihydroxybutyrophenone, uric acid andderivatives thereof, mannose and derivatives thereof, zinc andderivatives thereof (e.g. ZnO, ZnSO₄), selenium and derivatives thereof(e.g. selenium methionine), stilbenes and derivatives thereof (e.g.stilbene oxide, trans-stilbene oxide) and the derivatives (salts,esters, ethers, sugars, nucleotides, nucleosides, peptides and lipids)of said active ingredients which are suitable according to theinvention.

Any pharmaceutically acceptable buffering agents to adjust the pH of theaqueous liquid pharmaceutical compositions according to the invention tobe within the acceptable range for topical administration, preferably inthe range of 3.0 to 6.0, more preferably in the range of 3.5 to 5, canbe used. For example the inclusion in the composition of apharmaceutically acceptable acid such as acetic, citric, fumaric,phosphoric, hydrochloric, lactic or nitric acids or the like, or amixture thereof. It will also be understood that certain compositions ofthe invention can have a pH in the desired range without inclusion of apH adjusting agent specifically for that purpose. Typically, however, anacidic buffer system is present in the composition to achieve thedesired pH. An acidic buffer system comprises an acidulant and abuffering agent. Suitable acidulants will be known to those of skill inthe art and illustratively include acetic, citric, fumaric,hydrochloric, phosphoric, lactic and nitric acids and the like, andmixtures thereof. Suitable buffering agents will likewise be known tothose of skill in the art and illustratively include potassiummetaphosphate, potassium phosphate, sodium phosphate, sodium acetate,sodium citrate and the like, and mixtures thereof.

Suitable emollients, which can be used in the composition of the presentinvention include, for example, dodecane, squalane, cholesterol,isohexadecane, isononyl isononanoate, PPG Ethers, petrolatum, lanolin,safflower oil, castor oil, coconut oil, cottonseed oil, palm kernel oil,palm oil, peanut oil, soybean oil, polyol carboxylic acid esters,derivatives thereof, and the like, and combinations thereof.

Examples of suitable penetration enhancing agents can include, e.g.,dimethylsulfoxide (DMSO), N-methylpyrrolidine, dimethyl formamide (DMF),allantoin, urazole, N,N-dimethylacetamide (DMA), decylmethylsulfoxide,polyethylene glycol monolaurate, propylene glycol, propylene glycolmonolaurate, glycerol monolaurate, lecithin, the 1-substitutedazacycloheptan-2-ones, particularly 1-n-dodecylcyclazacycloheptan-2-one,alcohols, glycerin, hyaluronic acid, transcutol, and the like, andcombinations thereof. Certain oil components (e.g., certain vegetableoils such as, e.g., safflower oil, cottonseed oil and corn oil) also canexhibit penetration enhancing properties.

Examples of suitable preservatives to prevent microbial contaminationare alkylparabens, particularly methylparaben, propylparaben andbutylparaben; sodium benzoate; butylated hydroxy toluene; butylatedhydroxyanisole; ethylenediamine tetraacetic acid; chlorobutanol; benzylalcohol; phenylethylalcohol; dehydroacetic acid; sorbic acid; potassiumsorbate; benzalkonium chloride; benzethonium chloride; and mixturesthereof. The amount of preservative generally utilized will varydepending upon the preservative selected.

Examples of solubilizing agents are, for example, nonionic surfactantsfrom at least one of the following groups: products of the addition of 1to 30 moles of ethylene oxide and/or 0 to 5 moles of propylene oxideonto linear C₈-C₂₂ fatty alcohols, C₁₂-C₂₂ fatty acids and alkyl phenolscontaining 8 to 15 carbons in the alkyl group; alkyl and/or alkenyloligoglycosides containing 8 to 22 carbons in the alkyl group andethoxylated analogs thereof; addition products of 1 to 15 moles ofethylene oxide with castor oil and/or hydrogenated castor oil; additionproducts of 15 to 60 moles of ethylene oxide with castor oil and/orhydrogenated castor oil; partial esters of glycerol and/or sorbitan withunsaturated or saturated, linear or branched fatty acids containing 12to 22 carbons and/or hydroxycarboxylic acids containing 3 to 18 carbonatoms and addition products thereof with 1 to 30 moles of ethyleneoxide; mixtures of alkoxylated glycerides and alkoxylated glycerine,partial esters of polyglycerol (average degree of selfcondensation 2 to8), polyethylene glycol (weight average molecular weight 400 to 5000),trimethylolpropane, pentaerythritol, sugar alcohols (for examplesorbitol), alkyl glucosides (for example methyl glucoside, butylglucoside, lauryl glucoside) and polyglucosides (for example cellulose)with saturated and/or unsaturated, linear or branched fatty acidscontaining 12 to 22 carbons and/or hydroxycarboxylic acids containing 3to 18 carbons and addition products thereof with 1 to 30 moles ofethylene oxide; mixed esters of pentaerythritol, fatty acids, citricacid and fatty alcohol and/or mixed esters of fatty acids containing 6to 22 carbons, methyl glucose and polyols, preferably glycerol orpolyglycerol; mono-, di- and trialkyl phosphates and mono-, di- and/ortri-PEG-alkyl phosphates and salts thereof; block copolymers, forexample Polyethyleneglycol-30 Dipolyhydroxystearate; polymeremulsifiers; polyalkylene glycols and alkyl glyceryl ethers.Particularly preferred solubilizing agents are products of the additionof 1 to 30 moles of ethylene oxide and/or 0 to 5 moles of propyleneoxide onto linear C₈-C₂₂ fatty alcohols such as lauryl, myristyl, cetyl(palmityl), stearyl, oleyl, and ricinoleyl alcohols, or technical grademixtures thereof such as cetostearyl alcohol or palmitoleyl alcohol.

A thickening agent or viscosity-enhancing agent can be included togenerally thicken the liquid pharmaceutical compositions. While anysuitable thickening agent can be included in the compositions of thepresent invention, a preferred thickening agent, when used, includes oneor more of acacia, alginic acid bentonite, carbomer,carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methylcellulose, ethylcellulose, glycerin, gelatin guar gum,hydroxyethylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose, maltodextrin, polyvinyl alcohol, povidone,propylene carbonate, propylene glycol alginate, sodium alginate, sodiumstarch glycolate, starch tragacanth, and xanthan gum, and anycombination thereof. More preferred thickening agents are glycerin,hydroxypropylmethylcellulose, and xanthan gum, and any combinationthereof.

Examples of wetting agents (chemical substances that increase thespreading and penetrating properties of a liquid by lowering its surfacetension) include one or more cationic surfactants, such as benzalkoniumchloride; non-ionic surfactants such as polyoxyethylene andpolyoxypropylene block copolymers; polyoxyethylene fatty acid glyceridesand oils (such as polyoxyethylene (6) caprylic/capric mono- anddiglycerides), polyoxyethylene (40) hydrogenated castor oil;polyoxyethylene sorbitan esters, such as polysorbate 20 and polysorbate80; propylene glycol fatty acid esters, such as propylene glycollaureate; glyceryl fatty acid esters, such as glyceryl monostearate;sorbitan esters, such as sorbitan monolaurate, sorbitan monooleate,sorbitan monopalmitate and sorbitan monostearate; glyceryl fatty acidesters, for example glyceryl monostearate; anionic surfactants such assodium lauryl sulphate, sodium lauryl ether sulphate; or fatty acids andsalts thereof, such as oleic acid, sodium oleate and triethanolamineoleate.

The invention further relates to a topical pharmaceutical composition asdefined above for use in the treatment or prevention of psoriasis,atopic dermatitis (atopic eczema) and other skin disorders or diseases,such as contact dermatitis, seborrheic dermatitis, xerotic eczema,dyshidrosis, discoid eczema, venous eczema, dermatitis herpetiformis,neurodermatitis or autoeczematization.

The topical pharmaceutical composition of the invention is preferablyformulated in the form of a cream.

The invention further relates to the use of a topical pharmaceuticalcomposition as defined above for the manufacture of a medicament for thetreatment or prevention of psoriasis, atopic dermatitis (atopic eczema)and other skin disorders or diseases, such as contact dermatitis,seborrheic dermatitis, xerotic eczema, dyshidrosis, discoid eczema,venous eczema, dermatitis herpetiformis, neurodermatitis orautoeczematization.

The invention further relates to a method for treating a subjectafflicted with psoriasis, atopic dermatitis (atopic eczema) and otherskin disorders or diseases, such as contact dermatitis, seborrheicdermatitis, xerotic eczema, dyshidrosis, discoid eczema, venous eczema,dermatitis herpetiformis, neurodermatitis or autoeczematization, whichcomprises applying to the affected area of skin of said subject aneffective amount of a topical pharmaceutical composition as definedabove.

The method of using the topical pharmaceutical composition of theinvention is by applying it to completely cover the affected area,forming an occlusive barrier. The usual frequency of application is oncedaily, although adequate maintenance therapy for some patients may beachieved with less frequent application.

The following examples are given in order to provide a person skilled inthe art with a sufficiently clear and complete explanation of thepresent invention, but should not be considered as limiting of theessential aspects of its subject, as set out in the preceding portionsof this description.

EXAMPLES Example 1

A cream according to the invention was prepared having the compositionindicated in Table 1 (wt. % based on the total weight of thecomposition)

TABLE 1 Mometasone furoate cream Ingredients wt. % Mometasone furoate0.1 Liquid Paraffin 17.5 White Soft Paraffin 26.5 Cetostearyl Alcohol¹7.2 Macrogol Cetostearyl Ether² 2.8 Cetyl Alcohol 1.0 Hexylene Glycol10.0 Glycerol 1.0 Xanthan Gum 0.1 Purified Water up to 100% pH adjustedto 3.5-4.5 ¹Emulsifiying Cetostearyl Alcohol Type A ²Having 20-30 unitsof ethylene oxide per molecule

Said cream was prepared in the following manner:

1) Oil phase: white soft paraffin, liquid paraffin, cetostearyl alcohol,macrogol cetostearyl ether and cetyl alcohol were added to a main vesselequipped with anchor stirrer and homogeniser. The ingredients wereheated to 70° C. and melted while stirring until obtaining an homogenousmixture.2) Xanthan gum phase: Xanthan gum was pre-dispersed in hexylene glycol.3) Water phase: About 90 wt. % of the total amount of water was added toa stainless steel container and heated to 70° C. A pH adjuster was addedto the water and dissolved while stirring. The xanthan gum phase (step2) was added while homogenizing.4) Combination: The hot aqueous phase of step (3) was transferred to themain vessel while stirring and subsequent homogenizing.5) The combined phases were cooled down to 25° C. while stirring.6) Mometasone furoate was pre-dispersed in glycerol. This dispersion wasdiluted with the remaining purified water and then transferred to theemulsion while homogenizing.

Example 2

The viscosity of the cream of Example 1 was measured at 20° C. using aDIN-Rotations Rheometer (Paar Physica); Measuring System Z 3 DIN; D=571/s.

Additionally, the viscosity of a commercially available mometasone creamsuch as ECURAL® Fettcreme 0.1% of Essex Pharma GmbH (ComparativeExample 1) using the same measuring conditions.

According to the product information, each gram of ECURAL® Fettcreme0.1% contains: 1 mg mometasone furoate in a cream base of hexyleneglycol; phosphoric acid; propylene glycol stearate; stearyl alcohol andceteareth-20; titanium dioxide; aluminum starch octenylsuccinate; whitewax; white petrolatum; and purified water. The water content of ECURAL®Fettcreme is about 3 to 5 wt. %.

The results are indicated in Table 2.

TABLE 2 Viscosity values Example 1 Comparative Example 1 aprox. 5,000mPa · s aprox. 20,000 mPa · s

From the experimental results it can be concluded that the cream ofExample 1 (according to the invention) can be more easily applied thanthe cream of Comparative Example 1 (commercially available)

Example 3

A vasoconstrictor assay measuring skin blanching (assay described byMckenzie and Stoughton, Arch. Dermatol., 86, 608-610 (1962)) was used todetermine the bioequivalence of the cream of Example 1 (according to theinvention) to ECURAL® Fettcreme 0.1% (Comparative Example 1)

Study population: 30 Subjects with healthy skin in the area of the testfields, demonstrating adequate vasoconstriction to corticosteroids, aged18 years or older, were investigated.

Test performance: Single topical non-occlusive application to testfields located on the volar surface of the forearms. Skin colour in thetreated and untreated test fields was measured using chromametry. Inaddition, the degree of vasoconstriction was clinically assessedcompared to the untreated test fields.

Efficacy: Under the conditions in the present vasoconstrictive assay thetopical bioavailability of the cream of Example 1 was shown by a strongblanching effect. The strong blanching effect of the cream of Example 1was comparable to the effect of Comparative Example 1. Similar mean AUCswere noted for the cream of Example 1 (according to the invention) andfor Comparative Example 1 (commercially available). The topicalbioavailability of the active formulations was shown by chromametricmeasurement and clinical assessment.

Example 4

A psoriasis bio-assay for topical corticosteroid activity-psoriasisplaque test (assay described by Dumas and Scholtz, Acta Dermatovener(Stockh), 52, 43-48 (1972)) was also used to determine thebioequivalence of the cream of Example 1 (according to the invention) toECURAL Cream 0.1% (Comparative Example 1).

Twenty-two male or female subjects were enrolled. The test fields onpsoriatic skin were descaled and treated occlusively over a study periodof 12 days.

The cream of Example 1 demonstrated a strong positive effect in thetreatment of psoriasis. The antipsoriatic effect of the cream of Example1 was comparable to the effect seen for Comparative Example 1 on thebasis of the sonographic measurements and global clinical assessment. Noclinical improvement was seen for the active ingredient-free vehicle.

1. A topical pharmaceutical composition comprising, based on the totalweight of the composition: a) 0.01 to 0.2 wt. % of mometasone furoate,b) 5 to 18 wt. % of hexylene glycol, c) 20 to 40 wt. % of water, and d)25 to 70 wt. % of an oil phase.
 2. The composition according to claim 1,wherein the total amount of a) mometasone furoate is in the range of0.05 to 0.15 wt. %, based on the total weight of the composition.
 3. Thecomposition according to claim 1, wherein the total amount of b)hexylene glycol is in the range of 7 to 15 wt. %, based on the totalweight of the composition.
 4. The composition according to claim 1,wherein the total amount of c) water is in the range of 25 to 40 wt. %,based on the total weight of the composition.
 5. The compositionaccording to claim 1, wherein the total amount of d) oil phase is in therange of 30 to 65 wt. %, based on the total weight of the composition.6. The composition according to claim 1, comprising, based on the totalweight of the composition: a) 0.05 to 0.15 wt. % of mometasone furoate,b) 7 to 15 wt. % of hexylene glycol, c) 25 to 35 wt % of water, and d)30 to 65 wt. % of an oil phase.
 7. The composition according to claim 6,comprising, based on the total weight of the composition: a) 0.05 to0.15 wt. % of mometasone furoate, b) 7 to 15 wt. % of hexylene glycol,c) 25 to 35 wt. % of water, d1) 32 to 50 wt. % of petroleumhydrocarbons, d2) 5 to 12 wt. % of C₆-C₂₄ fatty alcohols, and d3) 0.1 to5 wt. % of polyols other than hexylene glycol.
 8. The compositionaccording to claim 7, comprising, based on the total weight of thecomposition: a) 0.08 to 0.12 wt. % of mometasone furoate, b) 8 to 13 wt.% of hexylene glycol, c) 26 to 34 wt. % of water, d1) 35 to 48 wt % ofpetroleum hydrocarbons chosen from liquid paraffin, white soft paraffinand mixtures thereof, d2) 7 to 10 wt. % of C₆-C₂₄ fatty alcohols chosenfrom lauryl alcohol, miristyl alcohol, palmityl alcohol, stearylalcohol, oleyl alcohol and mixtures thereof, and d3) 0.5 to 3 wt. % ofglycerol.
 9. The composition according to claim 1, wherein thecomposition further comprises anti-irritants agents, antioxidantsagents, buffering agents, chelating agents, emollients, penetrationenhancing agents, preservative agents, solubilizing agents, thickeningagents, wetting agents or mixtures thereof.
 10. The compositionaccording to claim 1, wherein the composition has a pH value in therange of 3.0 to 6.0.
 11. The composition according to claim 1, whereinthe composition is formulated in the form of a cream.
 12. (canceled) 13.(canceled)
 14. A method for treating a subject afflicted with psoriasis,atopic dermatitis or other skin disorders or diseases, comprisingapplying to the affected area of skin of said subject an effectiveamount of the composition of claim
 1. 15. The composition according toclaim 2, wherein the total amount of a) mometasone furoate is in therange of 0.08 to 0.12 wt. %, based on the total weight of thecomposition.
 16. The composition according to claim 3, wherein the totalamount of b) hexylene glycol is in the range of 8 to 13 wt. %, based onthe total weight of the composition.
 17. The composition according toclaim 4, wherein the total amount of c) water is in the range of 25 to35 wt. %, based on the total weight of the composition.
 18. Thecomposition according to claim 17, wherein the total amount of c) wateris in the range of 26 to 34 wt. %, based on the total weight of thecomposition.
 19. The composition according to claim 7, comprising, basedon the total weight of the composition: a) 0.08 to 0.12 wt. % ofmometasone furoate, b) 8 to 13 wt. % of hexylene glycol, c) 26 to 34 wt.% of water, d1) 35 to 48 wt. % of petroleum hydrocarbons, d2) 7 to 10wt. % of C₆-C₂₄ fatty alcohols, and d3) 0.5 to 3 wt. % of polyols otherthan hexylene glycol.